Is RDH12 p.Ala166= (c.498C>A) pathogenic?

RDH12 p.Ala166= (c.498C>A) is classified Likely benign in RDH12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-09). Very rare (popmax 0.000847%, nfe); Associated with Leber congenital amaurosis 13.

What condition is associated with RDH12 p.Ala166= (c.498C>A)?

RDH12 p.Ala166= (c.498C>A) is associated with Leber congenital amaurosis 13 (ClinVar).

How common is RDH12 p.Ala166= (c.498C>A) in the general population?

RDH12 p.Ala166= (c.498C>A) is very rare (popmax 0.000847%, nfe) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

RDH12 p.Ala166=

c.498C>A · rs1244771115 · VCV757194

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Conditions

Leber congenital amaurosis 13

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.62	GERP -2.9, phastCons 0.044
Overall
CADD	5.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,040 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,694 alleles · very rare exomes 11/1,461,378 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)grpmax	0.000847%	118,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RDH12
Protein: p.Ala166=
Coding: c.498C>A
MANE Select: NM_152443
dbSNP: rs1244771115
Type: single nucleotide variant
Location: chr14:67727030 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.21

Full RDH12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RDH12 p.Ala166fs Pathogenic/Likely pathogenic ★★ same residue
RDH12 c.68+1G>A Pathogenic ★★ same condition
RDH12 p.Ala206Asp Likely pathogenic ★★ same condition
RDH12 p.Ala47Thr Pathogenic/Likely pathogenic ★★ same condition
RDH12 p.Asn147Thr Likely pathogenic ★★ same condition
RDH12 p.Glu77Ter Pathogenic/Likely pathogenic ★★ same condition
RDH12 p.Leu93Pro Pathogenic/Likely pathogenic ★★ same condition
RDH12 p.Tyr194Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rdh12-p-ala166 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown